Entering Syracuse University, Rubell had the intention of becoming a dentist, but failed his courses and switched majors, studying finance and history. Rubell was reportedly not a good student but managed to complete his studies, eventually completing a master's degree in finance. While attending college, Rubell met Ian Schrager, who became a lifelong friend and business partner. Rubell, along with Schrager, were brothers together at the university's Sigma Alpha Mu fraternity.[2]

Rubell and Schrager opened two clubs, one in Boston with John Addison from La Jardin, the other, called The Enchanted Garden, in Queens in 1975, which later became Douglaston Manor. In April 1977, they opened Studio 54 in the old CBS Studio on West 54th Street that the network was selling. Rubell became a familiar face in front of the building, turning people away and only allowing entry to those who met his pedantic standards. Rubell also dealt with the club's celebrity patrons, ensuring that they were thrown lavish parties. His approach worked and the club made $7 million during its first year.

In December 1978, Studio 54 was raided after Rubell was quoted as saying that only the Mafia made more money than the club brought in. In June 1979, Rubell and Schrager were charged with tax evasion, obstruction of justice, and conspiracy for reportedly skimming nearly $2.5 million in unreported income from the club's receipts, in a system Rubell called "cash-in, cash-out and skim." Police reports state that cash and receipts were in the building and were hidden in the ceiling sections of Rubell's office, where both he and Schrager worked.[3] A second raid occurred in December 1979. The pair hired Roy Cohn to defend them,[4] but on January 18, 1980, they were sentenced to three and a half years in prison and a $20,000 fine each for the tax evasion charge. On February 4, 1980, Rubell and Schrager went to prison and Studio 54 was sold in November of that year for $4.75 million. On January 30, 1981, Rubell and Schrager were released from prison after which they lived at a halfway house for two and half months.[5]

In 1985, Rubell, who was closeted for most of his life, discovered he had contracted HIV which later progressed to AIDS. He began taking AZT, but his illness was furthered by his continued drug usage and drinking, which affected his already-compromised immune system. A few weeks before his death, Rubell checked into Beth Israel Medical Center in New York City under an assumed name to seek treatment for severe peptic ulcers, kidney failure and hepatitis.[5] He died there on July 25, 1989. Rubell's official cause of death is listed as hepatitis and septic shock complicated by AIDS.[3][7]